Current Pharmaceutical Design - Volume 15, Issue 21, 2009
Volume 15, Issue 21, 2009
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Editorial [Hot Topic: Therapeutic Potential of Peptide Motifs - Part II (Executive Editor: Jean-Claude Herve)]
More LessThe production of new molecular entities endowed with salutary medicinal properties is a formidable challenge; synthetic molecules that can bind with high sequence specificity to a chosen target in a protein or gene sequence are of major interest in medicinal and biotechnological contexts. The general awareness of the importance of peptides in physiology and pathophysiology has markedly increased over the last few years. With progresses in the analysis of whole genomes, the knowledge base in gene sequence and expression data useful for protein and peptide analysis has drastically increased. The medical need for relevant biomarkers is enormous. This is particularly true for the many types of cancers, but also for other diseases, e.g. type 2 diabetes or cardiac diseases, which also lack adequate diagnostic markers with high specificity and sensitivity. Imaging technologies for early detection of diseases, proteomic and peptidomic multiplex techniques have markedly evolved in recent years. Peptides can indeed be regarded as ideal agents (as “magic bullets”) for diagnostic and therapeutic applications because of their fast clearance, rapid tissue penetration, and low antigenicity, and also of their easy production, allowing innumerable biological applications. They can easily be engineered to improve their biological activities as well as their stability and their efficient delivery to specific targets. This second themed issue of Current Pharmaceutical Design, for which I have the honour to be Executive Guest Editor, addresses topical issues to some of these potential utilizations of peptide motifs for a variety of genetic and acquired diseases. A collection of biological processes protect both animal and plant kingdoms from pathogens and tumour cells, detecting a wide variety of agents (from viruses to parasitic worms), distinguishing them from the organism's own healthy cells and tissues. The protective immunity against pathogenic infection can be divided into innate and adaptive immunities, respectively representing the first defence barrier in the host and the second line defence including T (cellular) and B (humoral) cell mediated responses. Antimicrobial peptides (AMPs) are an essential part of innate immunity that evolved in living organisms over 2.6 billion years to combat microbial challenge, and their fundamental biological role in vivo has been proposed to be the elimination of pathogenic microorganisms, including Gram-positive and -negative bacteria, fungi, and viruses. Gill Diamond, Nicholas Beckloff, Aaron Weinberg and Kevin O. Kisich [1] summarise AMP structure and function and overview the varied activities of AMPs in mammals, which may help to understand their roles in innate host defence. AMPs found in the skin, beside their endogenous antibiotic ability, play important roles in normal skin function and in various skin conditions, overviewed by Francois Niyonsaba, Isao Nagaoka, Hideoki Ogawa and Ko Okumura [2], who also explore the future of AMPs as potential therapeutics for various infection- and/or inflammatory-related skin diseases. Growth factors (GFs), extracellular signalling polypeptides capable of stimulating cellular growth, proliferation and cellular differentiation, exert a wide spectrum of biological activities selectively binding to and activating specific membrane receptors which then transfer the message to cell interior, inducing specific biochemical pathways. GFs are especially involved in the regulation of angiogenesis, a physiological process of remodelling of the vascular tissue, characterized by the branching out of a new blood vessel from a pre-existing vessel, underlining several pathologies. Molecules interfering with the molecular recognition between a GF and its receptor, and able to modulate angiogenesis, have a big pharmacologic interest. Luca D. D'Andrea, Annarita Del Gatto, Lucia De Rosa, Alessandra Romanelli and Carlo Pedone [3] show how peptides are useful tools to develop new lead compounds disrupting protein-protein interface for pharmacological applications.
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The Roles of Antimicrobial Peptides in Innate Host Defense
Authors: Gill Diamond, Nicholas Beckloff, Aaron Weinberg and Kevin O. KisichAntimicrobial peptides (AMPs) are multi-functional peptides whose fundamental biological role in vivo has been proposed to be the elimination of pathogenic microorganisms, including Gram-positive and -negative bacteria, fungi, and viruses. Genes encoding these peptides are expressed in a variety of cells in the host, including circulating phagocytic cells and mucosal epithelial cells, demonstrating a wide range of utility in the innate immune system. Expression of these genes is tightly regulated; they are induced by pathogens and cytokines as part of the host defense response, and they can be suppressed by bacterial virulence factors and environmental factors which can lead to increased susceptibility to infection. New research has also cast light on alternative functionalities, including immunomodulatory activities, which are related to their unique structural characteristics. These peptides represent not only an important component of innate host defense against microbial colonization and a link between innate and adaptive immunity, but also form a foundation for the development of new therapeutic agents.
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Multifunctional Antimicrobial Proteins and Peptides: Natural Activators of Immune Systems
Authors: Francois Niyonsaba, Isao Nagaoka, Hideoki Ogawa and Ko OkumuraIn addition to the physical barrier of the stratum corneum, cutaneous innate immunity also includes the release of various humoral mediators, such as cytokines and chemokines, recruitment and activation of phagocytes, and the production of antimicrobial proteins/ peptides (AMPs). AMPs form an innate epithelial chemical shield, which provides a front-line component in innate immunity to inhibit microbial invasion; however, this might be an oversimplification of the diverse functions of these molecules. In fact, apart from exhibiting a broad spectrum of microbicidal properties, it is increasingly evident that AMPs display additional activities that are related to the stimulation and modulation of the cutaneous immune system. These diverse functions include chemoattraction and activation of immune and/or inflammatory cells, the production and release of cytokines and chemokines, acceleration of angiogenesis, promotion of wound healing, neutralization of harmful microbial products, and bridging of both innate and adaptive immunity. Thus, better understanding of the functions of AMPs in skin and identification of their signaling mechanisms may offer new strategies for the development of potential therapeutics for the treatment of infection- and/or inflammation-related skin diseases. Here, we briefly outline the structure, regulation of expression, and multifunctional roles of principal skin-derived AMPs.
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Peptides Targeting Angiogenesis Related Growth Factor Receptors
Authors: Luca D. D'Andrea, Annarita Del Gatto, Lucia De Rosa, Alessandra Romanelli and Carlo PedoneGrowth factors (GFs) are extracellular signaling polypeptides regulating cell proliferation, differentiation and survival. They exert a wide spectrum of biological activities selectively binding to and activating specific membrane receptors which then transfer the message to cell interior inducing specific biochemical pathways. GFs are especially involved in the regulation of angiogenesis, a physiological process underlining several pathologies. Molecules able to modulate angiogenesis, interfering with the molecular recognition between a GF and its receptor, have a big pharmacologic interest. Either GF and the receptor are potential drug target. Peptides are useful molecules to develop new lead compounds disrupting protein-protein interface for pharmacological applications. In this review we describe peptides targeting the receptors of the pro-angiogenic growth factors FGF, PDGF and VEGF. The biological function and the structure of each growth factor/receptor system are discussed, as well as the molecular interaction between peptides and the receptors. Finally, we highlight the pharmacological and diagnostic applications of these peptides in angiogenesis related diseases.
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Naturally Occurring and Synthetic Peptides Acting on Nicotinic Acetylcholine Receptors
Authors: Igor E. Kasheverov, Yuri N. Utkin and Victor I. TsetlinNicotinic acetylcholine receptors (nAChRs) are pentameric membrane-bound proteins belonging to the large family of ligandgated ion channels. nAChRs possess various binding sites which interact with compounds of different chemical nature, including peptides. Historically first peptides found to act on nAChR were synthetic fragments of snake α-neurotoxins, competitive receptor antagonists. Later it was shown that fragments of glycoprotein from rabies virus, having homology to α-neurotoxins, and polypeptide neurotoxins waglerins from the venom of Wagler's pit viper Trimeresurus (Tropidolaemus) wagleri bind in a similar way, waglerins being efficient blockers of muscle-type nAChRs. Neuropeptide substance P appears to interact with the channel moiety of nAChR. β-Amyloid, a peptide forming senile plaques in Alzheimer's disease, also can bind to nAChR, although the mode of binding is still unclear. However, the most well-studied peptides interacting with the ligand-binding sites of nAChRs are so-called α-conotoxins, peptide neurotoxins from marine snails of Conus genus. First α-conotoxins were discovered in the late 1970s, and now it is a rapidly growing family due to isolation of peptides from multiple Conus species, as well as to cloning, and chemical synthesis of new analogues. Because of their unique selectivity towards distinct nAChR subtypes, α-conotoxins became valuable tools in nAChR research. Recent X-ray structures of α- conotoxin complexes with acetylcholine-binding protein, a model of nAChR ligand-binding domains, revealed the details of the nAChR ligand-binding sites and provided the basis for design of novel ligands.
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Current Status and Perspectives in Peptide Receptor Radiation Therapy
Authors: Catherine Ansquer, Francoise Kraeber-Bodere and Jean F. ChatalRegulatory peptide receptors are overexpressed in numerous human cancers. The specific receptor binding property of peptides can be exploited by their labelling with a radionuclide and their use as carriers to guide the radioactivity to the tissues expressing their specific receptors. During the past decade, radiolabelled receptor-binding peptides have emerged as an important class of radiopharmaceuticals for tumour diagnosis and therapy. The first and most successful imaging agents to date are somatostatin analogues which are routinely used for somatostatin receptor scintigraphy. Peptide receptor radionuclide therapy (PRRT) with 90Y-DOTA-octreotide and 177Lu-DOTA-octreotate in neuroendocrine tumours (NETs) results in symptomatic improvement, prolonged survival, and enhanced quality of life. The results in terms of tumour regression are very encouraging with few and mostly mild side effects when patients are carefully selected and kidney protective agents are given. Nevertheless much profit can be gained from improving the available receptortargeting strategies and developing new strategies. In this review, the current state of clinical use of radiolabelled peptides for diagnosis and therapy of NETs is presented. In addition, potential directions for optimization and future developments are discussed. These include the optimization of peptide analogues or derivatives, increasing the access and binding on specific receptors on the tumour sites, increasing radiotoxicity profile and multimodality strategies. Other peptides such as minigastrin, glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), bombesin (BN)/gastrin-releasing peptide (GRP), substance P, neurotensin (NT), neuropeptide Y (NPY) and RGD peptides are promising for PRRT and currently under preclinical and clinical development.
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Peptide Inhibitors Targeting Protein Kinases
Authors: Hagit Eldar-Finkelman and Miriam EisensteinPhosphorylation by protein kinases is a central theme in biological systems. Aberrant protein kinase activity has been implicated in a variety of human diseases, therefore, modulation of kinase activity represents an attractive therapeutic approach for the treatment of human illnesses. Development and design of specific inhibitors for protein kinases thus became a major strategy in many drug discovery programs. Inhibition of protein kinase activity may be achieved by blocking the phosphorylation activity or by disrupting protein-protein interactions. Peptides that can mimic most truly these regulatory modes are favorite choice for protein kinase-targeting. Here we focus on important motifs regulating the protein kinase signaling network and described how they may be exploited for peptide drug design. Protein kinases are important regulators of most, if not all, biological processes. Their abnormal activity has been implicated as causal factors in many human diseases, including cancer, diabetes and neurodegenerative disorders [1-3]. Protein kinases are thus attractive targets for drug design and compounds that manipulate their cellular activity are of enormous therapeutic potential. With a target in hand, medicinal chemists can generate low molecular weight compounds that bind the target with high affinity and alter its biological behavior. In many cases, however, drugs fail as they lack appropriate pharmaceutical properties and are of limited specificity resulting in unfavorable side effects. Under these circumstances, the use of peptides, which copy ‘natural’ motifs that specifically influence kinase activity and/or its intracellular interactions with cognate partners, may be a promising approach for selective inhibition of protein kinases. In this review we focus on the strategies to design such peptide inhibitors, focusing mainly on the serine/threonine protein kinase family.
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Peptides as Signaling Inhibitors for Mammalian MAP Kinase Cascades
Authors: Matthias Gaestel and Michael KrachtMammalian MAPK cascades are essential for cellular signaling in response to mitogenic signals and stress-stimuli to regulate proliferation, differentiation and apoptosis. The three major MAPK cascades, ERK1/2-, JNK- and p38, maintain signaling specificity by scaffolding proteins and by specific docking interactions between pathway components. The structures mediating these interactions include the domain of versatile docking (DVD) responsible for MAP3K-MAP2K-interaction and the common docking (CD)-domain and the ED (glutamate/aspartate)-site of MAPKs together with the various docking (D) motifs in MAP2Ks, MAPK substrates and MAPKphosphatases. Several of these interactions have been studied in great detail. First approaches to use this knowledge to develop peptides that specifically inhibit MAPK signaling in disease models have been reported. It becomes obvious that specificity of peptides competing with kinase-docking is comparable to or even superior to small molecule ATP-competitive inhibitors. In addition to specifically targeting protein-protein interactions, the ultimate efficacy of these peptide inhibitors in vivo also depends on their delivery, stability and toxicity in living cells and in the whole organism.
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Targeting Rho GTPases by Peptidic Structures
Authors: Filippo Marchioni and Yi ZhengRho GTPases represent a family of small GTP-binding proteins that are involved in many important cellular functions relevant to cancer including cell cytoskeleton organization, migration, transcription, and proliferation. Since deregulation of members of Rho GTPase family is often found associated with many disease states, targeting of Rho GTPases and related signaling pathways for potential therapeutic benefits has been extensively pursued. Recent progress in this field of studies by peptide and peptidomemic inhibitors has provided important validations to this principle. The possibility to design and synthesize specific peptides that can bind to specific surface of the targeting proteins to elicit transient and specific blockade of the signal flows that require defined protein-protein interactions makes peptide inhibitors an attractive approach. In this review we summarize the recent advances in the design and application of a number of polypeptide and peptidomimetic structures that specifically target individual members of Rho GTPases and their up- or down-stream signaling regulators/effectors with an emphasis on cancer, inflammation and neurodegenerative diseases. The principle derived from the peptidic inhibitors has led to discoveries of the first generation of small molecule inhibitors of Rac GTPase of the Rho family. The implication of these studies in the pathobiology of various human diseases makes targeting Rho GTPases a valid strategy for future therapies.
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Modulating Proteostasis: Peptidomimetic Inhibitors and Activators of Protein Folding
Authors: Feras Hatahet and Lloyd W. RuddockProtein folding in the cell is a complex process with a fine balance between productive and non-productive folding. To modulate, either up-regulating or down-regulating, the level of one specific protein with multiple approaches is possible, including the modulation of catalysed protein folding, the use of chemical and pharmacological chaperones, alteration of natural protein-protein interactions, the regulation of degradative pathways and manipulation of natural control mechanisms, such as the heat shock response and the unfolded protein response. Errors in proteostasis are linked to a wide range of disease states and many examples exist of the successful manipulation of proteostasis for the partial or complete elimination of the disease phenotype, including for many amyloid based diseases such as Parkinson's and Alzheimer's as as well as for 'loss-of-function' diseases such as Fabry's and Gaucher's diseases. This review takes an overview of the different approaches that can be used to alter proteostasis with an emphasis on peptidomimetic inhibitors and activators of protein folding. It covers the modulators available, their mechanisms of action and potential limitations, including the problems of specificity in altering proteostasis.
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Therapeutic Potential of Peptide Motifs Against HIV-1 Reverse Transcriptase and Integrase
More LessMultiple clinical benefits have been obtained thanks to the combination of drugs targeting several steps of the HIV-1 replication. However, despite such combination therapy, complete eradication of the virus cannot be attained. Moreover, emergence of resistance observed under treatment and the lengthening life expectancy of treated patients highlight the need for new anti-HIV agents. Peptide- based compounds that exhibit anti RT and anti integrase activities were particularly described. Active peptides have been obtained from several ongoing approaches. The study of interaction between viral proteins inside the preintegration complex, and the growing knowledge of interactions between viral proteins and cellular partners, have generated a useful source of data for the development of peptide inhibitors. Recent data were also obtained from the observation that viral enzymes such as RT and integrase are fully active when they are in a dimeric (RT) or oligomeric state. Peptides derived from the interface of dimers are also of interest. The obtention of efficient small molecules as competitive oligomerization inhibitors is problematic, but anyway, improved cellular uptake and chemical modifications that were obtained in the past ten years allowed numerous peptide drugs to reach the clinic. Finally, a new promising class of peptide inhibitors is emerging called “shiftides”, which interfere with the ability of IN to adopt an oligomeric active state.
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Cyclin Dependent Kinases as Attractive Targets to Prevent Transcription from Viral Genomes
Authors: Fatah Kashanchi and Kylene Kehn-HallMost viral treatments target the virus itself, providing very specific effects and limiting side-effects on uninfected cells. However, this strategy of drug design often results in resistant viruses, especially among RNA viruses. Therefore, the focus has turned to drugs that target cellular proteins that are essential for viral replication, but not for cellular viability. Pharmacological CDK inhibitors are a prime example of this type of approach. Reviewed within are the various functions of CDKs, their role in the life cycle of selected Retroviruses and Herpesviruses, and the pharmacological CDK inhibitors that have been focused on in terms of viral inhibition.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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